Body Mass Index (BMI) has been recognized by the U.S. Department of Health as a reference relationship between a person's height and weight. To determine a person's Body Mass Index in kg/m2, the weight of the person, for example in pounds, is first multiplied by a conversion factor of 703 (with units of kilogram.inch2.pound−1. meter−2), and that result is then divided by the height of the person, in inches squared. Alternatively, when height is measured in meters (1 inch=0.0254 meters) and weight in kilograms (1 pound Avoirdupois (U.S.)=0.4536 kg), the conversion factor is unity, and the Body Mass Index is obtained directly in units of kg/m2.
Body Mass Index (BMI) can be used to determine when extra weight above an average or normal weight range for a person of a given height can translate into and signal increased probability for additional health risks for that person. Such health risks are considered to be related to the presence of additional weight above a desired range for that person.
Body Mass Index does not directly measure percent of body fat, although higher BMI's are usually associated with an increase in body fat, and thus excess weight. A BMI of 24 kg/m2 or less is a commonly accepted guideline used to define a person with a healthy weight and who is neither overweight or obese. A desired BMI range is from about 18 kg/m2 to about 24 kg/m2, wherein a person is considered to have a healthful weight for the person's height. A Body Mass Index reading under 20 kg/m2, and especially under 18 kg/m2, is frequently considered to signify that the person is underweight which can be unhealthy. A person with a BMI above 24 kg/m2, such as from about 25 kg/m2 to about 30 kg/m2, is frequently considered to be overweight, and a person with a BMI above about 35 kg/m2 is frequently considered to be obese In another aspect, an individual who has a BMI in the range of about 25 kg/m2 to about 35 kg/m2, and has a waist size of over 40 inches for a man and over 35 inches for a woman, is considered to be at especially high risk for health problems.
Health risks related to a person being overweight and health risks related to a person being obese represent rapidly growing threats to the health of populations in an increasing number of countries worldwide. Obesity is a disease that is prevalent in both developing and developed countries and that affects children and adults alike.
Information available from the American Heart Association related to statistical results of the Third National Health and Nutrition Examination Survey 1988–1994 suggests that among American children aged 6 to 11 years, the following percentages were overweight, using 95th percentile of body mass index (BMI) values: for non-Hispanic whites, 10.3 percent of boys and 9.2 percent of girls were overweight; for non-Hispanic blacks, 11.9 percent of boys and 16.4 percent of girls were overweight; and for Mexican Americans, 17.4 percent of boys and 14.3 percent of girls were overweight.
Among adolescents aged 12 to 17 years, the following percentages were overweight, using the 95th percentile of BMI values: for non-Hispanic whites, 11.1 percent of boys and 8.5 percent of girls were overweight; for non-Hispanic blacks, 10.7 percent of boys and 15.7 percent of girls were overweight; and for Mexican Americans, 14.6 percent of boys and 13.7 percent of girls were overweight.
Among adults aged 18 and older, the following people are overweight (defined as a body mass index (BMI) of 25 kg/m2 or higher): for non-Hispanic whites, over 62 percent of men and over 43 percent of women are overweight; for non-Hispanic blacks, over 64 percent of men and over 64 percent for women are overweight; for Hispanics, over 64 percent of men and over 56 percent of women are overweight; for non-Hispanic Asian/Pacific Islanders, over 35 percent of men and over 25 percent of women are overweight.
Among Americans aged 18 years and older, the median percentages of obesity are (defined as a body mass index or BMI greater than 30 kg/m2): for whites, about 15 percent; for blacks, about 26 percent; for Hispanics, about 18 percent; for Asian/Pacific Islanders, about 4.8 percent; and for American Indians/Alaska Natives, about 30 percent.
Among Americans aged 20 to 74 years, an age-adjusted prevalence of being overweight (i.e., having a BMI of 25.0 kg/m2 or higher) and of being obese (i.e., having a BMI of 30.0 kg/m2 or higher) are: for non-Hispanic whites, about 61 percent of men and about 47 percent of women are overweight, and about 21 percent of men and about 23 percent of women are obese; for non-Hispanic blacks, about 58 percent of men and about 68 percent of women are overweight, and about 21 percent of men and about 38 percent of women are obese; for Mexican Americans, about 69 percent of both men and women are overweight, and about 25 percent of men and about 36 percent of women are obese.
Among American Indians aged 45 to 74 years, about 26 percent of men and about 31 percent of women are overweight (defined as a BMI of about 28 kg/m2 to about 31 kg/m2 for men and about 27 kg/m2 to about 32 kg/m2 for women), and about 35 percent of American Indian men and about 41 percent of women are obese (defined as a BMI of about 31 kg/m2 or higher for men and a bout 32 kg/m2 or higher for women).
The year-to-year rate of increase in the number of overweight children and adolescents is about 2 to 3 percent. Each year an estimated 300,000 U.S. adults die of causes related to the health risk of obesity. Over 100 million American adults (over 56 million men and over 52 million women) are overweight with a BMI of about 25 kg/m2 and higher. Of these, over 44 million American adults (over 18 million men and over 25 million women) are obese, having a body mass index (BMI) of about 30 kg/m2 or higher. (Obesity Clinical Guidelines: NIH Statement Jun. 3, 1998, press release).
A person can be overweight but not obese if that person's BMI is between about 25 to 30 kg/m2, while a person who is obese with a BMI above 30 kg/m2 is also overweight.
In one aspect, in order to lessen the risk for health problems in an overweight person and to improve that person's health, it is desirable to provide compositions and methods useful in the treatment of an overweight person which produces a reduction in the person's body mass index (BMI), preferably from a level above 25 kg/m2 to a level below 25 kg/m2, and more preferably to a BMI level between 25 kg/m2 and 18 kg/m2.
In another aspect, in order to lessen the risk for health problems in an obese person and to improve that person's health, it is desirable to provide compositions and methods useful in the treatment of an obese person which produce a reduction in the person's body mass index (BMI), preferably from a level above 30 kg/m2 to a level below 30 kg/m2, more preferably to a level below 25 kg/m2, and most preferably to a BMI level between 25 kg/m2 and 18 kg/m2.
A person who has a BMI of between about 30 kg/m2 to about 25 kg/m2 is considered to be overweight, and a person who has a BMI of greater than about 30 kg/m2 is considered to be clinically obese. Both genetic and environmental factors can contribute to a person becoming overweight or obese. The most common cause of weight gain that can produce elevations in a person's BMI that are synonymous to being overweight and/or obese is a high caloric food intake especially in the absence of exercise or physical activity. The resulting accumulation of surplus fat places overweight or obese individuals at increased risk of illness such as hypertension, lipid disorders, type 2 diabetes, cardiovascular diseases, high blood pressure, elevated levels of cholesterol, hyperlipidemia, coronary heart disease, stroke, gallbladder disease, osteoarthritis, joint pain, sexual and fertility problems, sleep apnea and respiratory problems, skin conditions, certain type of cancers, and a wide variety of other diseases and undesired physiological conditions, as well as overall mortality. An obese individual with a BMI above about 30 kg/m2 is up to about fourteen times more likely to die at a significantly younger age than a lean person with a BMI below 25 kg/m2. Obesity creates a high-risk medical burden on society and its treatment would be highly desirable. Eliminating or reducing obesity would also decrease medical costs for treating many co-morbid conditions.
The biochemical mechanisms related to adipogenesis, to becoming overweight and to becoming obese are complex and comprise a number of interactions between ligands and their receptors, such as leptin, NPY monoamines (dopamine, serotonin, and norepinephrine), and CART (i.e., cocaine amphetamine regulated transcript), and others.
The obesity phenotype is probably connected to over 250 genes, markers and chromosomal regions in the human genome. Commonly used markers for adipocyte differentiation include aP2 (fatty acid binding protein), GPDH (glycerol-3-phosphate dehydrogenase), and adipsin. Regulatory factors that influence adipogenesis by influencing transcription include the CAAT enhancer-binding proteins a, b, d (C/EBP a, -b, -d), peroxisome proliferator-activated receptors (e.g., PPARgamma), sterol response element binding proteins (SREBP), and preadipocyte factor 1 (pref-1). The progression of adipocyte differentiation can be characterized by a number of genetic changes involving expression of early, intermediate, and late genes.
Adipogenesis is a multistep organogenenic process that begins in the prenatal period, but unlike osteogenesis and myogenesis, the adipogenesis process never ends. In this process, mesenchymal cells can proliferate in clonal expansion, and at some point, some of these cells can differentiate into preadipocytes or cells committed to fill with lipid (i.e., fat) and then become adipocytes. When preadipocytes undergo a differentiation step and begin to fill with lipid, lipid first accumulates within the cell in small droplets (multilocular cells) and eventually the droplets fuse into one large droplet (unilocular cells). The adipocyte can continue to enlarge by accumulating additional lipid. A typical mesenchymal cell is 10 to 20 μm in diameter, but adipocytes can easily reach 100 μm (and in some cases 200 μm) in diameter. The volume of the cell can increase as much as a thousand fold largely because of lipid accumulation.
Obesity is the result of numerous, interacting behavioral, physiological, and biochemical factors. One increasingly important factor is the generation of additional fat cells, or adipocytes, in response to excess feeding or intake of food, especially food high in fat or comprising fat or fat pre-metabolites, and/or large increases in body fat composition. The generation of new adipocytes is controlled by several adipocyte-specific transcription factors that regulate preadipocyte proliferation and adipogenesis. Generally these adipocyte-specific factors are expressed following the induction of adipogenesis.
Reusch et al. in Mol Cell Biol. 2000 February; 20 (3): 1008–1020 noted that transcription factor(s) involved in initiating adipocyte differentiation had not been identified, but described how the transcription factor, CREB, was constitutively expressed in preadipocytes and throughout the differentiation process. They noted that CREB was stimulated by conventional differentiation-inducing agents such as insulin, dexamethasone, and dibutyryl cAMP. Stably transfected 3T3-L1 preadipocytes (L1 cells) were generated in which they could induce the expression of either a constitutively active CREB (VP16-CREB) or a dominant-negative CREB (KCREB). Inducible expression of VP 16-CREB alone was sufficient to initiate adipogenesis as determined by triacylglycerol storage, cell morphology, and the expression of two adipocyte marker genes, peroxisome proliferator activated receptor gamma 2, and fatty acid binding protein. KCREB alone blocked adipogenesis in cells treated with conventional differentiation-inducing agents. These data suggested that activation of CREB was necessary and sufficient to induce adipogenesis. CREB was shown to bind to putative CRE sequences in the promoters of several adipocyte-specific genes. These data also suggested CREB as a primary regulator of adipogenesis.
Insulin can play a role in controlling adipogenesis. Several factors exert positive and negative influences on the process of adipogenesis. When insulin binds to its receptor it causes a signal cascade that ultimately leads to the translocatation of GLUT-4 receptors to cell surface membranes to allow glucose to be taken up by the cells.
Understanding weight regulation involves, in part, unraveling the roles played by insulin and leptin in regulating appetite control and energy expenditure in the brain. Both of these blood-borne signals provide information to the brain about fat storage. Homeostasis and glucose metabolism is ultimately regulated in the hypothalamus, specifically in the arcuate nucleus (ARC) region. Two subsets of neurons in the ARC express receptors for insulin and leptin and are believed to effect metabolism through an anabolic/catabolic regulation pathway. The proposed catabolic circuit involves the proopiomelanocortin (POMC) expressing neurons. These are activated by insulin and leptin causing the release of the neuropeptide α-MSH, believed to increase energy expenditure and reduce food intake. Neuropeptide Y (NPY) and agouti related protein (AgRP) expressing neurons complete the anabolic circuit becoming activated by low levels of insulin and leptin, stimulating downstream neurons to increase food intake and energy storage (i.e., increase insulin levels). Insulin and leptin satisfy criteria required for adiposity signals: secretion into plasma in proportion to body fat stores, transport into the brain from the bloodstream, expression of signal-transducing molecules in brain areas that control energy homeostasis, and the ability to reduce food intake upon central administration.
One potential cause of obesity is a resistance or desensitization of receptors to insulin and leptin in the blood, which results in an increase of food intake and body adiposity as well as glucose intolerance, hyperleptinemia, and reproductive abnormalities. Several factors can play a role in determining cell sensitivity to insulin.
Thiazolidinediones can increase insulin sensitivity, while several substances including tumor necrosis factor (TNF-α), growth hormone, plasminogen-activator inhibitor-1, angiotensin 2, free fatty acids, and the hormone resistin can decrease insulin sensitivity. Insulin can up-regulate resistin gene expression, possibly serving as a negative feedback loop, while isoproterenol, the cytokine TNF-α, and activation of β-adrenoceptors suppress resistin expression and secretion. TNF-α can act as a regulator of adipocytes, and may be involved in the development of Type II diabetes as well as obesity.
Available treatments for obesity can produce undesirable and serious side effects or such treatments may lack efficacy. Obesity and overweight conditions may become partially reversed or prevented by employing diet or nutrition and behavior modification programs or by administration of pharmaceutical therapeutic (drug) compositions. Widely administered drugs include orlistat, which reduces the amount of dietary fat that is absorbed from the intestine; sibutramine, which suppresses appetite by inhibiting the re-uptake of norepinephrine and serotonin; fenfluramine and d-fenfluramine, which suppress appetite by both releasing serotonin and then inhibiting its re-uptake; and phentermine, which suppresses the appetite by stimulating the release of norepinephrine.
Drug therapies for weight reduction usually achieve only a 5% to 10% decrease in body weight (National Task Force on the Prevention and Treatment of Obesity: Long-term pharmacotherapy in the Management of Obesity, JAMA 276:1907–15, 1996).
Many drugs produce mild to serious side effects in overweight and obese patients. Common side effects include dizziness, headaches, rapid pulse, palpitations, sleeplessness, hypertension, diarrhea, and intestinal cramping. The combination of fenfluramine and phentermine, which produced a 15% to 20% reduction in body weight (F. Brenot et al., Appetite Suppressant Drugs and the Risk of Primary Pulmonary Hypertension, N. Engl. J. Med., 335:609–16, 1996), also provided an increased the risk of heart valve damage and a number of confirmed patient deaths related to “Fen-Phen”.
Medications used for weight loss can fall into two groups: those that reduce the absorption of nutrients into the body and those that reduce appetite and thereby decrease food intake.
Adipose tissue produces leptin that reaches homeostatic hypothalamic centers in the brain and provides information on the state of the energy balance. Adipocytes play a critical role in the storage of energy as lipid and in the overall regulation of the body's metabolism. That adipocytes are endocrine cells that have a profound effect on human physiology has been postulated for over 40 years. Recent studies indicate that obesity affects about 30% of the population and that obesity has been identified as a risk factor for metabolic diseases such as type 2 diabetes, hypertension, and hyperlimidia. A better understanding of human adipocyte biology is critical to the development of pharmacological agents to treat these devastating diseases.
Orlistat (branded as Xenical) was approved by the FDA for reducing nutrient absorption. Agonasts are known to induce lipolysis, and thereby have the potential to offer weight-lowering properties. Beta-agonists, such as isoproterenol and turbataline, have been shown to increase lipolysis, leading to an increase in energy expenditure and a decrease in fat stores. Beta-agonists can also modulate glucagon and insulin secretion, liver metabolism and glucose uptake in muscle via beta-adrenergic receptors (beta2adrenergic receptor, beta3adrenergic receptor). In addition, polymorphisms of the beta3adrenergic receptor may be involved in insulin resistance and hypoglycemeia. However, use of beta-agonist can also lead to hyperglycemia, or an increase in blood sugar levels as well as insulin desensitization.
A number of weight loss drugs have been marketed, but most have undesired side effects for the patient. For example, a combination of amphetamine and dextroamphetamine, branded as Adderall, is a sympathomimetic amine appetite suppressant with high abuse potential. Benzphetamine, branded as Didrex or Benzfetamine, is a sympatho- mimetic amine appetite suppressant also with high abuse potential. Bromocriptine, branded as Ergoset or Parlodel, stimulates dopamine type-2 receptors and antagonizes type-1 receptors in brain, but it is not approved for treatment of obesity although it is used off label. Dexfenfluramine, branded as Redux, acts as an appetite suppressant via serotonin release and serotonin reuptake block, but it was voluntarily withdrawn from the market because of evidence of heart valve damage. Dextroamphetamine, branded as Dexedrine, is a sympathomimetic amine appetite suppressant used off-label for obesity although it is highly abused. Diethylpropion, branded as Amfepramone and Tenuate, is a sympatho-mimetic amine appetite suppressant with a possible link to primary pulmonary hypertension. Fluoxetine, branded as Prozac, is a selective serotonin reuptake inhibitor (SSRI) that is used off-label. Mazindol, branded Mazanor and Sanorex, is a sympathomimetic amine appetite suppressant subject to high abuse potential. Methamphetamine, branded as Desoxyn or Methampex, is a sympathomimetic amine appetite suppressant subject to high abuse potential. Orlistat, branded as Xenical, is not a CNS-active drug but can decrease the amount of fat absorbed from the diet by about 30%. However, the drug may have a link to breast cancer. Other sympathomimetic amine appetite suppressants include Phendimetrazine, Phentermine which was approved as a resin complex, and Phenylpropanolamine which is available over the counter. Additionally, Sibutramine, branded as Meridia inhibits reuptake of dopamine, norepinephrine, and serotonin in the brain.
In addition to the above types of drug therapeutic agents, a number of herbal weight reduction formulas have also been suggested as alternatives to both prescription and over-the-counter weight loss compounds. Formulations containing herbal components can have fewer side effects than prescription and over-the-counter medications, but some herbal formulas can still be abused. For example, improper administration of herbal weight loss formulas based primarily on ma huang (ephedra) and high caffeine-containing herbs, such as guanrana and kola nut, may result in diminished energy and a depleted body.
U.S. Pat. No. 6,541,046 describes an herbal composition for hindering weight gain comprising: rhubarb, turmeric, astragalus root, red sage root, and ginger root.
U.S. Pat. No. 6,322,823 describes an aromatherapy composition directed to combat symptoms of premenstrual syndrome (PMS) comprising externally applied highly concentrated essential oils extracted from plant cells. The composition can comprise a mixture of essential oil of geranium, essential oil of clary sage, and essential oil of orange, and can be applied directly on the skin or in a carrier.
Given the prevalence and serious problems associated with obesity, and the significant drawbacks associated with many weight loss compounds, a need exists for a means to discover compounds and compositions that are safe and effective in the treatment of persons that are overweight or obese to reduce weight gain, cause weight loss, and reduce body mass index to acceptably healthy levels in the range of 25 to 18 kg/m2.